Abstract
Parkinson's disease (PD) is a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies, the major components of which are filaments consisting of alpha-synuclein. Two recently identified point mutations in alpha-synuclein are the only known genetic causes of PD. alpha-Synuclein fibrils similar to the Lewy body filaments can be formed in vitro, and we have shown recently that both PD-linked mutations accelerate their formation. This study addresses the mechanism of alpha-synuclein aggregation: we show that (i) it is a nucleation-dependent process that can be seeded by aggregated alpha-synuclein functioning as nuclei, (ii) this fibril growth follows first-order kinetics with respect to alpha-synuclein concentration, and (iii) mutant alpha-synuclein can seed the aggregation of wild type alpha-synuclein, which leads us to predict that the Lewy bodies of familial PD patients with alpha-synuclein mutations will contain both, the mutant and the wild type protein. Finally (iv), we show that wild type and mutant forms of alpha-synuclein do not differ in their critical concentrations. These results suggest that differences in aggregation kinetics of alpha-synucleins cannot be explained by differences in solubility but are due to different nucleation rates. Consequently, alpha-synuclein nucleation may be the rate-limiting step for the formation of Lewy body alpha-synuclein fibrils in Parkinson's disease.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies, the major components of which are filaments consisting of ␣-synuclein
Once nuclei are formed, the aggregates grow rapidly until a thermodynamic equilibrium between aggregate and monomer is reached. Under these steady state conditions the growth equilibrium constant describes the solubility of the protein, which is equivalent to its critical concentration [16]
␣-synuclein nucleation may be the rate-limiting step for the formation of Lewy body ␣-synuclein fibrils in Parkinson’s disease. In this light it was of interest to show that nuclei formed of mutant ␣-synuclein can function as a seed for elongation by wild type ␣-synuclein, which is a situation similar to the one found in familial PD cases
Summary
Once nuclei are formed, the aggregates grow rapidly (elongation phase) until a thermodynamic equilibrium between aggregate and monomer is reached Under these steady state conditions the growth equilibrium constant describes the solubility of the protein, which is equivalent to its critical concentration [16]. The critical concentrations of wild type and mutant ␣-synuclein do not differ significantly, suggesting that the accelerated aggregation of the ␣-synuclein mutations is not due to a decreased solubility of mutant monomer or increased stability of mutant fiber, respectively, but rather due to different nucleation rates. ␣-synuclein nucleation may be the rate-limiting step for the formation of Lewy body ␣-synuclein fibrils in Parkinson’s disease In this light it was of interest to show that nuclei formed of mutant ␣-synuclein can function as a seed for elongation by wild type ␣-synuclein, which is a situation similar to the one found in familial PD cases
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